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Dissociation between resistance to apoptosis and the transformed phenotype in IGF-I receptor signaling
G Romano1, M Prisco, T Zanocco-Marani
1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Abstract:
Programmed Cell Death (PCD) is known to play an important role in both the development and the growth rate of human tumors. It has in fact been suggested that suppression of the apoptotic pathway is a requirement for the establishment of the transformed phenotype. In order to elucidate the relationship between resistance to apoptosis and transformation, we have asked in this investigation whether or not the two processes can be directly correlated. For this purpose, we have used mouse embryo fibroblasts (MEF) expressing either the wild-type or several mutants of the type 1 insulin-like growth factor receptor (IGF-IR). The wild-type IGF-IR has both transforming and anti-apoptotic activities, and we have asked whether these two activities can be or not separated in mutant receptors. Using this well-defined system, our results show that certain mutants of the IGF-IR that have strong anti-apoptotic and mitogenic activities, are incapable of transforming MEF (colony formation in soft agar). We have, instead, a good correlation between mitogenic and anti-apoptotic activities, suggesting the possibility that the two processes may share similar signaling pathways from the IGF-IR. On the other hand, our results indicate that transformation requires an additional signal, above and beyond the mitogenic and survival signals. Our conclusion is that, at least in this system, the establishment of the malignant phenotype and resistance to apoptosis can be dissociated, implying the possibility of separate targeting.
Insights
Programmed cell death (PCD) suppression is crucial for tumor growth. This study found that while some insulin-like growth factor receptor mutants promote survival and cell division, they do not cause transformation, suggesting separate pathways for apoptosis resistance and malignancy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Programmed cell death (PCD) is critical for tumor development and growth rate.
- Suppression of apoptosis is considered essential for establishing the transformed phenotype in cancer.
Purpose of the Study:
- To investigate the direct correlation between resistance to apoptosis and cellular transformation.
- To determine if the transforming and anti-apoptotic activities of the type 1 insulin-like growth factor receptor (IGF-IR) can be separated in mutant forms.
Main Methods:
- Utilized mouse embryo fibroblasts (MEF) expressing wild-type or mutant IGF-IR.
- Assessed the transforming potential (colony formation in soft agar) and anti-apoptotic/mitogenic activities of IGF-IR mutants.
Main Results:
- Certain IGF-IR mutants exhibited strong anti-apoptotic and mitogenic activities but failed to transform MEF.
- A strong correlation was observed between mitogenic and anti-apoptotic activities, suggesting shared signaling pathways from IGF-IR.
- Cellular transformation appears to require an additional signal beyond mitogenic and survival signals.
Conclusions:
- The establishment of the malignant phenotype and resistance to apoptosis can be dissociated.
- These findings imply that apoptosis resistance and transformation may be regulated by distinct signaling pathways, offering potential for separate therapeutic targeting.